Monday, October 17, 2011

Optimal Rectal Microbicide Design

via AIDS: Official Journal of the International AIDS Society, by Herrera, Carolinaa; Cranage, Martina; McGowan, Ian; Anton, Peter; Shattock, Robin J


Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a strategy to develop an effective rectal microbicide, we performed an ex-vivo preclinical evaluation to determine the efficacy and limitation of multiple combinations of reverse transcriptase inhibitors (RTIs).


A nucleotide, PMPA (tenofovir), a nucleoside, FTC (emtricitabine), RTIs and two nonnucleoside RTIs, UC781 and TMC120 (dapivirine), were used in double, triple and quadruple combinations against a panel of CCR5-uing and CXCR4-using clade B HIV-1 isolates and against RTI-escape variants.


Indicator cells and colorectal tissue explants were used to assess antiviral activity of drug combinations.


All combinations inhibited the isolates tested in a cellular model and in colorectal explants and produced, for at least one of the compounds, a change in the dose–response curve. Double and triple combinations incrementally augmented activity, even against RTI-escape mutants, whereas quadruple combinations conferred little further advantage.


The colorectal explant model may be used to identify the best candidate molecules and their combinations at the preclinical stage. Furthermore, this study demonstrates that combinations based on RTIs with different HIV-1 inhibitory mechanisms have potential as colorectal microbicides.

[If an item is not written by an IRMA member, it should not be construed that IRMA has taken a position on the article's content, whether in support or in opposition.]

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